Aim To report on the three-year safety, tolerability, clinical efficacy, and functional outcomes of atogepant for the preventive treatment of migraine from the phase 3, 156-week, open-label safety extension study in participants with chronic migraine (CM) or episodic migraine (EM) who had a prior inadequate response to two to four classes of conventional oral, non-migraine-specific preventive migraine treatments. Methods This was a 156-week, long-term, open-label extension (OLE) safety study in adult participants with either CM or EM who completed the lead-in PROGRESS or ELEVATE trials, respectively. The primary outcome was safety and tolerability of atogepant. Clinical efficacy and functional outcomes were prespecified exploratory analyses. Clinical efficacy endpoints were change from baseline (CFB) in mean monthly migraine days (MMDs), mean monthly headache days (MHDs), mean monthly acute medication use days, and responder rates (CFB ≥ 50%, ≥ 75% or 100% reduction in MMDs). Functional outcomes included CFB in Activity Impairment in Migraine-Diary domain score and Migraine-Specific Quality of Life Questionnaire version 2.1 for 156 weeks. All participants received atogepant 60 mg once daily. Results Of 596 participants, 595 (PROGRESS, N = 325; ELEVATE, N = 270) were treated and included in the safety population, and 529 (PROGRESS, N = 285; ELEVATE, N = 244) were included in the modified intention-to-treat population. The mean duration of atogepant exposure was 808.1 days. Overall, 63.2% (376/595) of participants completed the 3-year open-label treatment period. Treatment-emergent adverse events (TEAEs) occurred in 83.2% (495/595) of participants. Common TEAEs (≥ 10%) were COVID-19 (33.6%, 200/595) and nasopharyngitis (15.5%, 92/595). Serious TEAEs occurred in 8.7% (52/595) of participants, including one death attributed to asphyxia from a house fire, and none were related to atogepant. TEAEs leading to study treatment discontinuation occurred in 6.7% (40/595) of participants. Alanine aminotransferase/aspartate aminotransferase ≥ 3× the upper limit of normal occurred in three participants; none met Hy's Law. Improvements in clinical efficacy and functional outcomes observed during the lead-in studies were maintained through 156 weeks. Post-baseline potentially clinically significant (PCS) weight loss of ≥ 7% from lead-in study baseline at any visit was reported in 37.2% (220/592) of participants, whereas 16.7% (99/592) reported PCS weight gain of ≥ 7%. Conclusions In this 3-year OLE study, atogepant was safe and well tolerated over three years for the preventive treatment of migraine in participants with CM and EM who had prior inadequate response to two to four classes of conventional oral, non-migraine-specific preventive migraine treatments. Overall safety results were consistent with the known safety profile of atogepant. No new safety signals were identified. Improvements in clinical efficacy and functional outcomes were maintained through 156 weeks. Trial Registration ClinicalTrials.gov NCT04686136; EudraCT Identifier 2020-002470-27.
Background Traditionally, migraine has been characterized by its paroxysmal attacks, with the interictal phase considered to be a symptom-free interval. However, emerging evidence suggests that the “migraine brain” remains in a state of altered neuro-excitability and impaired habituation between attacks, manifesting as debilitating interictal symptoms. This narrative review aims to describe the spectrum of interictal symptoms, their underlying mechanisms, and their impact on the cumulative disease burden, at the same time as exploring the implications for clinical management. Methods An extensive literature search of the PubMed database was performed using terms related to the migraine cycle, interictal phase, and disease burden. Original articles published within the last 10 years were prioritized, focusing on clinical trials, real-world evidence, and neurophysiological studies. Results Interictal symptoms, including sensory hypersensitivity (photophobia, phonophobia, osmophobia, allodynia), cognitive dysfunction (“brain fog”), vestibular symptoms, and affective dysregulation, affect between 26% and 76% of patients. These symptoms significantly contribute to the socioeconomic burden of migraine, leading to substantial productivity losses (absenteeism and presenteeism) and reduced quality of life. While non-specific preventives often fail to alleviate interictal symptoms, calcitonin gene-related peptide-pathway targeted therapies and onabotulinumtoxinA have demonstrated promising results in reducing the interictal burden, as measured by standardized tools such as the Migraine Interictal Burden Scale (MIBS-4). Conclusions Migraine management requires a paradigm shift from focusing solely on attack frequency to a more holistic approach that includes the interictal period. Standardizing interictal symptoms definitions and implementing specific outcome measures in clinical practice are essential to restore full functional capacity and provide comprehensive care for patients.
Aim To evaluate the short-term effectiveness and tolerability of gepants administered during active cluster headache (CH) bouts in routine clinical practice, focusing primarily on reduction in daily attack frequency and additionally on pain intensity, bout duration, and patient-reported outcomes. Methods We conducted an observational, uncontrolled, consecutive case series at a reference headache clinic. Patients fulfilling ICHD-3 criteria for episodic or chronic CH who initiated a standardized 28-day course of a gepant during an active bout between October 2024 and July 2025 were included. Baseline data were abstracted from clinical records and diaries. No systemic corticosteroids, greater occipital nerve blocks, preventive dose adjustments, or new preventives were introduced during the 28-day period. The primary endpoint was ≥50% reduction in mean daily attack frequency at the end of treatment compared with baseline. Secondary outcomes included change in pain intensity (Numerical Rating Scale, NRS), change in attack duration, impact on overall bout duration, Patient Global Impression of Change (PGIC), and adverse events. Analyses were descriptive. Results Ten patients were included (seven episodic CH [ECH], three chronic CH [CCH]). Median baseline attack frequency was three attacks/day (range 1–6), and median baseline NRS was 8.5. The primary endpoint was achieved in 7/10 patients (70.0%): 5/7 with ECH (71.4%) and 2/3 with CCH (66.7%). Two ECH patients with a low baseline frequency (two attacks/day) did not meet the ≥50% criterion but demonstrated marked reductions in pain intensity and shortened bout duration. Overall, pain intensity improved in 9/10 patients (90.0%), with a median NRS reduction of 7 points (range 0–10). Median intensity reduction was greater in ECH (7 points; range 2–10) than in CCH (2.5 points; range 0–5). Shortening of individual attacks was reported in 4/10 (40.0%), and reduction in overall bout duration in 7/10 (70.0%), predominantly among ECH. Median time to perceived benefit was 96 h. Adverse events were mild (nausea or constipation in 2/10). Conclusion In this small real-world case series, short-term gepant use during active cluster bouts was associated with multidimensional clinical improvement, particularly in episodic CH. Benefits extended beyond attack frequency to include substantial reductions in pain intensity and apparent modulation of bout duration. Given the uncontrolled design and limited sample size, findings should be interpreted cautiously but support further prospective, phenotype-stratified investigation.
Background Cluster headache (CH) is a highly disabling primary headache disorder characterized by severe unilateral attacks occurring in bouts. Calcitonin gene-related peptide plays a key role in CH pathophysiology, yet preventive treatment options remain limited. We aimed to evaluate the short-term clinical effects of atogepant in patients with episodic CH during an active cluster bout. Methods We conducted a single-center real-world observational study. The study protocol included both retrospective and prospective cohorts, but all patients in the present analysis were from the retrospective cohort. Adult patients with episodic CH treated with atogepant during an active bout were consecutively included. Weekly headache outcomes during baseline (the week prior to treatment) and week 1 after atogepant initiation were compared. The primary outcome was change in weekly headache days; secondary outcomes included attack frequency, pain intensity, attack duration, and acute medication use. Responder rates (≥ 50% reduction) and Patient Global Impression of Change (PGIC) were assessed. Results Eighteen patients were included (mean age 39.9 ± 11.2 years; 72.2% male). Significant improvements were observed across all outcomes within one week after atogepant initiation. Weekly headache days decreased from 7.0 (5.0–7.0) to 3.0 (2.0–7.0) ( p = 0.008), and attack frequency from 7.5 (5.5–14.0) to 3.0 (2.0–7.0) ( p = 0.018). Pain intensity, attack duration, and acute medication use were also reduced. Large effect sizes were observed (r = 0.56–0.79). A ≥ 50% reduction in headache days occurred in 50.0% of patients and in attack frequency in 81.2%. PGIC ratings indicated that 66.7% of patients were rated as much or very much improved. Discussion In this open-label, uncontrolled study, atogepant initiation was associated with short-term improvements across multiple headache outcomes within one week in patients with episodic CH. Given the small sample size, retrospective data collection, short follow-up, and concurrent preventive therapies, these preliminary findings require confirmation in randomized, placebo-controlled trials.
